Rational drug therapy is made difficult by large interpatient variability in response to drugs, and inherited differences in drug clearance and drug interactions contribute to this. This proposal is directed at improving our understanding of mechanisms of variable drug response based on genetics and drug interactions through the study of cytochrome P450 (CYP) 2B6. CYP2B6 is an enzyme that has been studied less than other CYPs, but one that plays a central role in the metabolism of many clinically important drugs and the drug interactions that ensue. We hypothesize that CYP2B6 genetic variations influence not only the clearance of and response to many drugs but also the relative susceptibility of CYP2B6 during drug-drug interactions. Studies in the PI's laboratory have identified a specific probe of CYP2B6 activity (efavirenz) and the most common and functionally important variant allele (CYP2B6*6) defining tagSNPs (G516T and A785G). In vitro and clinical studies are outlined in this proposal to test the influence of CYP2B6*6 allele on efavirenz metabolism and drug interactions. In aim one, we will test the hypothesis that the CYP2B6*6 allele influences baseline CYP2B6 activity and alters response to inhibition in vitro. Efavirenz metabolism and susceptibility to inhibitors will be determined in microsomes from human livers genotyped for the CYP2B6*6 allele. In aim two, we will test the hypothesis that the CYP2B6*6 allele influences CYP2B6 activity in vivo by measuring the metabolism of efavirenz (100 mg single oral dose). In aim three, we will test the hypothesis that the CYP2B6*6 allele influences responsiveness to inhibitory drug interactions in vivo. The effect of voriconazole (a newly identified inhibitor by the PI) on efavirenz (100 mg single dose) pharmacokinetics will be determined in healthy volunteers genotyped for the CYP2B6*6 allele. In aim four, we will test the hypothesis that the CYP2B6*6 allele influences steady-state exposure of drugs that undergo "autoinduction" of their metabolism, and thereby the drug interactions associated with them. 1) Single- and multiple- dose pharmacokinetics of efavirenz will be determined in healthy volunteers genotyped for the CYP2B6*6 allele; 2) the activity of selected CYPs will be assessed before and after multiple doses of efavirenz. Together, these studies will lay the groundwork for improved therapy with a growing list of drugs that are metabolized by CYP2B6 through optimizing beneficial effects and avoiding adverse drug reactions. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]